Expression of NMDA receptor and microRNA-219 in rats submitted to cerebral ischemia associated with alcoholism

ABSTRACT

Alcohol consumption aggravates injuries caused by ischemia. Many molecular mechanisms are involved in the pathophysiology of cerebral ischemia, including neurotransmitter expression, which is regulated by microRNAs.

Objective:

To evaluate the microRNA-219 and NMDA expression in brain tissue and blood of animals subjected to cerebral ischemia associated with alcoholism.

Methods:

Fifty Wistar rats were divided into groups: control, sham, ischemic, alcoholic, and ischemic plus alcoholic. The expression of microRNA-219 and NMDA were analyzed by real-time PCR.

Results:

When compared to the control group, the microRNA-219 in brain tissue was less expressed in the ischemic, alcoholic, and ischemic plus alcoholic groups. In the blood, this microRNA had lower expression in alcoholic and ischemic plus alcoholic groups. In the brain tissue the NMDA gene expression was greater in the ischemic, alcoholic, and ischemic plus alcoholic groups.

Conclusion:

A possible modulation of NMDA by microRNA-219 was observed with an inverse correlation between them.

RESUMO

Algumas condições podem agravar os danos causados pelo processo isquêmico, tais como o consumo de álcool, e diversos mecanismos moleculares que estão envolvidos na fisiopatologia da isquemia cerebral, incluindo a expressão de neurotransmissores, e estes podem estar regulados por microRNAs.

Objetivo:

Avaliar a expressão de NMDA e do microRNA-219 no tecido cerebral e no sangue de animais submetidos à isquemia cerebral associada ao alcoolismo.

Métodos:

50 ratos Wistar foram divididos em: controle, sham, isquêmico, alcoólico e isquêmico mais alcoólico. A expressão de microRNA-219 e de NMDA foram analisadas por PCR em tempo real.

Resultados:

Quando comparado com o grupo controle, o microRNA-219 no tecido cerebral foi menos expresso nos grupos isquêmico, alcoólico e associado. No sangue, este microRNA teve menor expressão no grupo alcoólico e no associado. Em relação à expressão do gene do NMDA, em tecido cerebral foi maior nos grupos isquêmico, alcoólico e no associado.

Conclusão:

Uma possível modulação de NMDA pelo microRNA-219 foi observada, com uma correlação inversa entre eles.

Keywords:

brain ischemia - alcoholism - N-Methylaspartate - microRNAs

Palavras-chave:

isquemia encefálica - alcoolismo - N-Metilaspartato - microRNAs

• References

• 1 Lotufo PA. Mortalidade pela doença cerebrovascular no Brasil. Rev Bras Hipertens. 2000;7(4):387-91.
• 2 Kim MW, Bang MS, Han TR, Ko YJ, Yoon BW, Kim JH et al. Exercise increased BDNF and trkB in the contralateral hemisphere of the ischemic rat brain. Brain Res. 2005;1052(1):16-21. doi:10.1016/j.brainres.2005.05.070
• 3 Bronner LL, Kanter DS, Manson JE. Primary prevention of stroke. N Engl J Med. 1995;333(21):1392-400. doi:10.1056/NEJM199511233332106
• 4 Harper C. The neuropathology of alcohol-related brain damage. Alcohol. 2009;44(2):136-40. doi:10.1093/alcalc/agn102
• 5 Ohsawa M, Tanno K. Conflicting effect of alcohol on cardiovascular risk: a clue to understand the different etiologies of coronary artery disease, stroke and peripheral artery disease. Hypertens Res. 2013;36(1):16-8. doi:10.1038/hr.2012.152
• 6 Sathyan P, Golden HB, Miranda RC. Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium. J Neurosci. 2007;27(32):8546-57. doi:10.1523/JNEUROSCI.1269-07.2007
• 7 Conti A, Aguennouz M, La Torre D, Tomasello C, Cardali S, Angileri FF et al. miR-21 and 221 upregulation and miR-181b downregulation in human grade II-IV astrocytic tumors. J Neurooncol. 2009;93(3):325-32. doi:10.1007/s11060-009-9797-4
• 8 Mendell JT. MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle. 2005;4(9):1179-84. doi:10.4161/cc.4.9.2032
• 9 Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 2008;39(3):959-66. doi:10.1161/STROKEAHA.107.500736
• 10 Saugstad JA. MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab. 2010;30(9):1564-76. doi:10.1038/jcbfm.2010.101
• 11 Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 2009;29(4):675-87. doi:10.1038/jcbfm.2008.157
• 12 Kye MJ, Neveu P, Lee YS, Zhou M, Steen JA, Sahin M et al. NMDA mediated contextual conditioning changes miRNA expression. PLoS One. 2011;6(9):e24682. doi:10.1371/journal.pone.0024682
• 13 Pai B, Siripornmongcolchai T, Berentsen B, Pakzad A, Vieuille C, Pallesen S et al. NMDA receptor-dependent regulation of miRNA expression and association with Argonaute during LTP in vivo. Front Cell Neurosci. 2014;7:285. doi:10.3389/fncel.2013.00285
• 14 Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA. 2009;106(9):3507-12. doi:10.1073/pnas.0805854106
• 15 Wibrand K, Panja D, Tiron A, Ofte ML, Skaftnesmo KO, Lee CS et al. Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur J Neurosci. 2010;31(4):636-45. doi:10.1111/j.1460-9568.2010.07112.x
• 16 Liu DZ, Tian Y, Ander B P, Xu H, Stamova BS, Zhan X et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab. 2010;30(1):92-101. doi:10.1038/jcbfm.2009.186
• 17 Zeng L, Liu J, Wang Y, Wang L, Weng S, Tang Y et al. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci (Elite Ed). 2011;3:1265-72. doi:10.2741/330
• 18 Chandrasekar R. Alcohol and NMDA receptor: current research and future direction. Front Mol Neurosci. 2013;6:14. doi:10.3389/fnmol.2013.00014
• 19 Zhao H, Mayhan WG, Arrick DM, Xiong W, Sun H. Dose-related influence of chronic alcohol consumption on cerebral ischemia/reperfusion injury. Alcohol Clin Exp Res. 2011;35(7):1265-9. doi:10.1111/j.1530-0277.2011.01461.x
• 20 Trudell JR, Messing RO, Mayfield J, Harris RA. Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci. 2014;35(7):317-23. doi:10.1016/j.tips.2014.04.009
• 21 Gorini G, Nunez YO, Mayfield RD. Integration of miRNA and protein profiling reveals coordinated neuroadaptations in the alcohol-dependent mouse brain. PLoS One. 2013;8(12):e82565. doi:10.1371/journal.pone.0082565
• 22 Mantha K, Laufer BI, Singh SM. Molecular changes during neurodevelopment following second-trimester binge ethanol exposure in a mouse model of fetal alcohol spectrum disorder: from immediate effects to long-term adaptation. Dev Neurosci. 2014;36(1):29-43. doi:10.1159/000357496
• 23 Tirapelli DPC, Carlotti Jr CG, Leite J P, Lizarte FS, Tirapelli L F, Colli BOC. Analysis of the NMDA in focal cerebral ischemia inrats. Int J Morphol. 2012;30:979-85. doi:10.4067/S0717-95022012000300035